title: Expression of an anti-RNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of antinucleic acid autoantibodies, high levels of circulating type I interferon (IFN-I), and an IFN-I-dependent elevated expression of activating FcγR. Increases in neutrophils and monocytes are often observed in clinical SLE, but how these contribute to autoantibody and IFN-I production is poorly understood. Here, we analyzed SLE pathogenesis in 564Igi mice, an SLE-model strain carrying gene-targeted heavy and light chain antibody genes encoding an anti-RNA autoantibody in a C57BL/6 background. Similar to human SLE patients, 564Igi mice produce anti-RNA autoantibodies and expanded neutrophil and monocyte populations. These myeloid cells produced IFN-I and exhibit increased FcγRIV expression induced via an IFN-I autocrine loop. A direct effect of IFN-I on 56 Igi BM B cells and neutrophils was supported by their upregulation of "IFN-I signature genes". In addition, 564Igi developing B cells showed upregulated TLR7 resulting in IgG2a/2b class switch recombination and autoantibody production. Our results indicate that the production of anti-RNA autoantibody is sufficient to induce an increase of BM, blood, and spleen IFN-I-producing neutrophils, and suggest a mechanism by which autoantibody and IFN-I contribute to SLE by activating B lymphocytes, neutrophils, and monocyte effector cells in vivo.
authors.affiliation: Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA.
authors.forename: Jin-Hwan
authors.initials: JH
authors.lastname: Han
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Umiker
authors.forename: Anastasia A
authors.initials: AA
authors.lastname: Kazimirova
authors.forename: Michael
authors.initials: M
authors.lastname: Fray
authors.forename: Parimal
authors.initials: P
authors.lastname: Korgaonkar
authors.forename: Erik
authors.initials: E
authors.lastname: Selsing
authors.forename: Thereza
authors.initials: T
authors.lastname: Imanishi-Kari
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D019898:Autocrine Communication; D001402:B-Lymphocytes / Q000276:immunology*; D048708:Cell Growth Processes / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D005803:Genes, Immunoglobulin / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D012313:RNA / Q000276:immunology; D017452:Receptors, IgG / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism
chemical_list: D001323:Autoantibodies; C496124:FCGR3A protein, human; D007074:Immunoglobulin G; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D012313:RNA
keywords: Autoantibody; Fcγ receptors; Myeloid cells; Systemic lupus erythematosus; Type I interferon (IFN-I)